Background: The extracellular microenvironment modulates cancer behavior. Although radiographic contrast enhancement is an ominous finding in gliomas, it remains unclear if the associated blood-brain barrier disruption merely reflects or functionally supports tumor aggressiveness. Methods: We utilized intra-operative microdialysis to sample the extracellular metabolome of radiographically diverse regions during fifteen neurosurgical resections. The global extracellular metabolome of recovered microdialysate was evaluated via ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and assessed using enrichment and correlation analyses. Results: Among 162 named metabolites identified via ultra-performance liquid chromatography tandem mass spectrometry, guanidinoacetate (GAA), was 126.32x higher in enhancing tumor than in adjacent brain. 48 additional metabolites were 2.05-10.18x more abundant in enhancing tumor than brain. With exception of GAA, and 2-HG in IDH-mutant gliomas, differences between non-enhancing tumor and brain microdialysate were comparatively modest and less consistent. The enhancing but not the non-enhancing glioma metabolome was significantly enriched for plasma-associated metabolites largely comprising amino acids and carnitines. Conclusions: Our findings suggest that metabolite diffusion through a disrupted blood-brain barrier may largely define the enhancing extracellular glioma metabolome. Future studies are needed to determine how the altered extracellular metabolome impacts glioma behavior.

中文翻译：

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血脑屏障破坏是否定义了胶质瘤细胞外代谢组？

背景：细胞外微环境调节癌症行为。尽管影像学对比增强是神经胶质瘤的不祥发现，但尚不清楚相关的血脑屏障破坏是否仅反映或在功能上支持肿瘤侵袭性。方法：我们利用术中微透析对十五次神经外科切除术中放射学不同区域的细胞外代谢组进行采样。通过超高效液相色谱串联质谱 (UPLC-MS/MS) 评估回收的微透析液的整体细胞外代谢组，并使用富集和相关分析进行评估。结果：在通过超高效液相色谱串联质谱法鉴定的 162 种命名代谢物中，胍基乙酸 (GAA) 为 126 种。增强肿瘤比邻近大脑高 32 倍。48 种额外的代谢物在增强肿瘤方面的丰度是大脑的 2.05-10.18 倍。除了 IDH 突变神经胶质瘤中的 GAA 和 2-HG，非增强肿瘤和脑微透析液之间的差异相对较小且不太一致。增强而非非增强神经胶质瘤代谢组显着富集了主要由氨基酸和肉毒碱组成的血浆相关代谢物。结论：我们的研究结果表明，通过破坏的血脑屏障的代谢物扩散可能在很大程度上定义了增强的细胞外神经胶质瘤代谢组。未来的研究需要确定改变的细胞外代谢组如何影响神经胶质瘤的行为。除了 IDH 突变神经胶质瘤中的 GAA 和 2-HG，非增强肿瘤和脑微透析液之间的差异相对较小且不太一致。增强而非非增强神经胶质瘤代谢组显着富集了主要由氨基酸和肉毒碱组成的血浆相关代谢物。结论：我们的研究结果表明，通过破坏的血脑屏障的代谢物扩散可能在很大程度上定义了增强的细胞外神经胶质瘤代谢组。未来的研究需要确定改变的细胞外代谢组如何影响神经胶质瘤的行为。除了 IDH 突变神经胶质瘤中的 GAA 和 2-HG，非增强肿瘤和脑微透析液之间的差异相对较小且不太一致。增强而非非增强神经胶质瘤代谢组显着富集了主要由氨基酸和肉毒碱组成的血浆相关代谢物。结论：我们的研究结果表明，通过破坏的血脑屏障的代谢物扩散可能在很大程度上定义了增强的细胞外神经胶质瘤代谢组。未来的研究需要确定改变的细胞外代谢组如何影响神经胶质瘤的行为。增强而非非增强神经胶质瘤代谢组显着富集了主要由氨基酸和肉毒碱组成的血浆相关代谢物。结论：我们的研究结果表明，通过破坏的血脑屏障的代谢物扩散可能在很大程度上定义了增强的细胞外神经胶质瘤代谢组。未来的研究需要确定改变的细胞外代谢组如何影响神经胶质瘤的行为。增强而非非增强神经胶质瘤代谢组显着富集了主要由氨基酸和肉毒碱组成的血浆相关代谢物。结论：我们的研究结果表明，通过破坏的血脑屏障的代谢物扩散可能在很大程度上定义了增强的细胞外神经胶质瘤代谢组。未来的研究需要确定改变的细胞外代谢组如何影响神经胶质瘤的行为。